Belatacept based immunosuppression: What and when to combine?

INTRODUCTION: This study examines the effect of belatacept based salvage regimens on kidney transplant outcomes. METHODS: This single-center retrospective study included all adult kidney transplant recipients between 2011 and 2022 who were converted to belatacept salvage therapy during their follow up. eGFR, graft survival, incidence of infections and neoplasia, histology and DSA data were collected through systematic review of the medical record. RESULTS: Patients were divided into 3 groups based on salvage regimen: Mycophenolate mofetil/belatacept (MMF/Bela) (n = 28), low-dose Calcineurin inhibitors/belatacept (CNI/Bela) (n = 22), and low-dose Calcineurin inhibitors/ Mycophenolate mofetil /belatacept (CNI/MMF/Bela) (n = 13). Patients with antibody-mediated rejection were more likely to receive CNIs in addition to belatacept (low-dose CNI/MMF/Bela 54%, low-dose CNI/Bela 45%, MMF/Bela 3.6%, p < 0.001). DSA decreased in all groups after transition to belatacept by 15.67% (p = 0.15). No difference in Glomerular filtration rate (eGFR) over time was observed between the groups, and eGFR remained stable over the first year after transition to belatacept. The incidence of death and allograft failure was similar between the groups (low- dose CNI/MMF/Bela n = 3, low-dose CNI/Bela n = 7, MMF/Bela n = 4; p = 0.41). Patients in the low-dose CNI/Bela cohort who were transitioned to belatacept within 6 months from transplant showed a decline in eGFR over the first year after transition, while the other treatment cohorts demonstrated stable or slight increase in eGFR. CONCLUSIONS: The present study demonstrates comparable transplant outcomes in terms of eGFR, graft survival, incidence of infections and neoplasia, rejection rate and donor specific antibody (DSA) in three belatacept-based maintenance immunosuppression regimens supporting the safety and efficacy of these therapeutic options.

Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients.

BACKGROUND: Belatacept has been demonstrated as an effective alternative immunosuppressant in kidney transplant recipients. This study focuses on outcomes of early and late conversion to Belatacept-based immunosuppression after kidney transplant. MATERIALS AND METHODS: This retrospective analysis of a prospectively collected database included all adult kidney transplants patients at SUNY Upstate Medical Hospital from 1 January 2014 to 30 December 2022. Early conversion was defined as all conversions done at <6 months after kidney transplantation, and late conversion to belatacept was defined as conversion at >6 months after kidney transplantation. RESULTS: Out of 61 patients included in this study, 33 patients (54%) were in the early conversion group, and 28 patients (46%) were in the late conversion group. The mean eGFR in the early conversion group was 26.73 ± 16.26 ml/min/1.73 m2 before conversion to belatacept, which improved to 45.3 ± 21.01 ml/min/1.73 m2 at one-year post-conversion (p = 0.0006). Furthermore, eGFR changes in the late conversion group were insignificant, with 46.30 ± 15.65 ml/min/1.73 m2 before conversion to belatacept, and 44.76 ± 22.91 ml/min/1.73 m2 after one year of follow-up (p = 0.72). All four biopsy-proven allograft rejections in the early conversion group were acute T-cell-mediated rejections (ATMR). In the late conversion group, out of three biopsy-proven rejections, one was chronic antibody-mediated rejection (CAMR), one was ATMR, and one was mixed ATMR/CAMR. All four patients with ATMR rejection received mycophenolic acid (MPA) as part of their immunosuppressive regimen, and none received tacrolimus. The one-year post-conversion allograft survival rate in early and late conversion groups was 100%. However, the one-year post-conversion patient survival rate was 90.9% in the early conversion group and 100% in the late conversion group (P = 0.11). CONCLUSIONS: Early post-transplant conversion to belatacept can improve the eGFR more meaningful when compared to late conversion. Patients who receive belatacept and MPA rather than tacrolimus may have increased rates of T-cell-mediated rejection.

Preoperative CT predictors of survival in patients with pancreatic ductal adenocarcinoma undergoing curative intent surgery.

PURPOSE: To evaluate the associations between computed tomography (CT) imaging features extracted from the structured American Pancreatic Association (APA)/Society of Abdominal Radiology (SAR) template and overall survival in patients with resected pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective analysis included consecutive patients with PDAC who consented to genomic tumor testing and underwent preoperative imaging and curative intent surgical resection from December 2006 to July 2017. Two radiologists assessed preoperative CT imaging using the APA/SAR PDAC-reporting template. Univariable associations between overall survival and imaging variables were evaluated using Cox proportional hazards regression. RESULTS: The study included 168 patients (66 years ± 11; 91 women). 126/168 patients (75%) received upfront surgical resection whereas 42/168 (25%) received neoadjuvant therapy prior to surgical resection. In the entire cohort, features associated with decreased overall survival were tumor arterial contact of any kind (hazard ratio (HR) 1.89, 95% CI 1.13-3.14, p = 0.020), tumor contact with the common hepatic artery (HR 2.33, 95% CI 1.35-4.04, p = 0.009), and portal vein deformity (HR 3.22, 95% CI 1.63-6.37, p = 0.003). In the upfront surgical group, larger tumor size was associated with decreased overall survival (HR 2.30, 95% CI 1.19-4.42, p = 0.013). In the neoadjuvant therapy group, the presence of venous collaterals was the only feature associated with decreased overall survival (HR 2.28, 95% CI 1.04-4.99, p = 0.042). CONCLUSION: The application of the APA/SAR pancreatic adenocarcinoma reporting template may identify predictors of survival that can aid in preoperative stratification of patients.

Post-treatment CT LI-RADS categories: predictors of overall survival in hepatocellular carcinoma post bland transarterial embolization.

PURPOSE: The LI-RADS Treatment Response (LR-TR) algorithm was introduced in 2017 to assist radiologists in assessing hepatocellular carcinoma (HCC) response following locoregional therapy. The objective of this study was to evaluate the associations between pre-treatment LI-RADS diagnostic categories, post-treatment LR-TR categories, and mRECIST response categories with overall survival (OS) of patients with HCC. METHODS: This retrospective study included untreated patients with one or two lesions who underwent transarterial embolization with or without concomitant ablation from December 2003 to December 2017. Two radiologists (R1 and R2) reviewed pre- and post-treatment CT imaging. Associations between pre- and post-treatment variables, including post-treatment LR-TR categories (Viable, Equivocal, Nonviable), with OS were assessed using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Eighty-five patients were included (median age = 71 years, range 50-87; 17 women). The median OS from first embolization was 43.92 months. Pre- and post-treatment tumor size, pre-treatment LR-TIV (compared with LR-5), and post-treatment LR-TR Viable (compared with LR-TR Nonviable) were associated with OS (p < 0.05 for all). Median OS was shorter for LR-TR Viable patients (R1, 25.64 months, 95% CI 18.58-35.70; R2, 26.43 months 95% CI 20.68-43.92) than for LR-TR Nonviable patients (64.21 months R1 and R2, 95% CI 42.71-92.45 and 36.30-94.09, respectively). mRECIST categories showed similar associations with OS. Inter-reader agreement was moderate for LI-RADS categories (κ = 0.57, 95% CI 0.35-0.78) and substantial for LR-TR categories (κ = 0.68, 95% CI 0.55-0.81). CONCLUSIONS: LR-TR categories show a strong association with OS in HCC patients treated with transarterial embolization.

Treatment of Chylous Ascites with Peritoneovenous Shunt (Denver Shunt) following Retroperitoneal Lymph Node Dissection in Patients with Urological Malignancies: Update of Efficacy and Predictors of Complications.

PURPOSE: We investigated the efficacy and analyzed the complication risk factors of peritoneovenous shunt in treating refractory chylous ascites following retroperitoneal lymph node dissection in patients with urological malignancies. MATERIALS AND METHODS: From April 2001 to March 2019 all patients with refractory chylous ascites after retroperitoneal lymph node dissection treated with peritoneovenous shunt were reviewed. Demographic characteristics, technical success, efficacy, patency period and complications were studied. Univariate and multivariate logistic regression analysis was performed to identify predictors of complications. RESULTS: Twenty patients were included in this study. Testicular cancer was the most common malignancy (85%). The mean number of days from surgery to detection of chylous ascites was 21 days (SD 15, range 4 to 65). Ascites permanently resolved after peritoneovenous shunt in 18 patients (90%), leading to shunt removal in 17 patients (85%) between 46 and 481 days (mean 162, SD 141). The mean serum albumin level increased 24% after shunt placement (mean 3.0±0.6 gm/dl before, 3.9±0.8 gm/dl after, p <0.05). The most common complication was occlusion (30%). Relative risk of complications increased significantly when shunt placement was more than 70 days after surgery and in patients with more than 5 paracenteses before peritoneovenous shunt placement (AR 0.71% vs 0.25%, RR 2.9, p <0.048 and AR 0.6% vs 0.125%, RR 4.8, p <0.04, respectively). CONCLUSIONS: Peritoneovenous shunt permanently treated chylous ascites in 90% of patients after retroperitoneal lymph node dissection. Peritoneovenous shunt was removed in 85% of patients. Shunt placement is an effective and safe treatment option for refractory chylous ascites. These patients might benefit from earlier intervention, after 4 to 6 weeks of conservative management as opposed to 2 to 3 months.

Clinical utility of radiomics at baseline rectal MRI to predict complete response of rectal cancer after chemoradiation therapy.

PURPOSE: To investigate the value of T2-radiomics combined with anatomical MRI staging criteria from pre-treatment rectal MRI in predicting complete response to neoadjuvant chemoradiation therapy (CRT). METHODS: This retrospective study included patients with locally advanced rectal cancer who underwent rectal MRI before neoadjuvant CRT from October 2011 to January 2015 and then surgery. Surgical histopathologic analysis was used as the reference standard for pathologic complete response. Anatomical MRI staging criteria were extracted from our institutional standardized radiology report. In radiomics analysis, one radiologist manually segmented the primary tumor on T2-weighted images for all 102 patients (i.e., training set); two different radiologists independently segmented 66/102 patients (i.e., validation set). 108 radiomics features were extracted. Then, scanner-independent features were identified and least absolute shrinkage operator analysis was used to extract a radiomics score. Finally, a support vector machine model combining the radiomics score and anatomical MRI staging criteria was compared against both anatomical MRI-only and radiomics-only models using the deLong test. RESULTS: The study included 102 patients (42 women; median age = 61 years).The radiomics score produced an area under the curve (AUC) of 0.75. Comparable results were found using the validation set (AUCs = 0.75 and 0.71 for each radiologist, respectively). The anatomical MRI-only model had an accuracy of 67% (sensitivity 42%, specificity 72%); when adding the radiomics score, the accuracy increased to 74% (sensitivity 58%, specificity 77%). CONCLUSION: Combining T2-radiomics and anatomical MRI staging criteria from pre-treatment rectal MRI may help to stratify patients based on the prediction of treatment response to neoadjuvant therapy.

Diagnostic accuracy of b800 and b1500 DWI-MRI of the pelvis to detect residual rectal adenocarcinoma: a multi-reader study.

PURPOSE: To compare the sensitivity, specificity and intra-observer and inter-observer agreement of pelvic magnetic resonance imaging (MRI) b800 and b1500 s/mm2 sequences in the detection of residual adenocarcinoma after neoadjuvant chemoradiation (CRT) for locally advanced rectal cancer (LARC). INTRODUCTION: Detection of residual adenocarcinoma after neoadjuvant CRT for LARC has become increasingly important and relies on both MRI and endoscopic surveillance. Optimal MRI diffusion b values have yet to be established for this clinical purpose. METHODS: From our MRI database between 2018 and 2019, we identified a cohort of 28 patients after exclusions who underwent MRI of the rectum before and after neoadjuvant chemoradiation with a protocol that included both b800 and b1500 s/mm2 diffusion sequences. Four radiologists experienced in rectal MRI interpreted the post-CRT MRI studies with either b800 DWI or b1500 DWI, and a minimum of 2 weeks later re-interpreted the same studies using the other b value sequence. Surgical pathology or endoscopic follow-up for 1 year without tumor re-growth was used as the reference standard. Descriptive statistics compared accuracy for each reader and for all readers combined between b values. Inter-observer agreement was assessed using kappa statistics. A p value of 0.05 or less was considered significant. RESULTS: Within the cohort, 19/28 (67.9%) had residual tumor, while 9/28 (32.1%) had a complete response. Among four readers, one reader had increased sensitivity for detection of residual tumor at b1500 s/mm2 (0.737 vs. 0.526, p = 0.046). There was no significant difference between detection of residual tumor at b800 and at b1500 for the rest of the readers. With all readers combined, the pooled sensitivity was 0.724 at b1500 versus 0.605 at b800, but this was not significant (p = 0.119). There was no difference in agreement between readers at the two b value settings (67.8% at b800 vs. 72.0% at b1500), or for any combination of individual readers. CONCLUSION: Aside from one reader demonstrating increased sensitivity, no significant difference in accuracy parameters or inter-observer agreement was found between MR using b800 and b1500 for the detection of residual tumor after neoadjuvant CRT for LARC. However, there was a suggestion of a trend towards increased sensitivity with b1500, and further studies using larger cohorts may be needed to further investigate this topic.

Prognostic impact of TTF-1 expression in patients with stage IV lung adenocarcinomas.

OBJECTIVES: Thyroid transcription factor 1 (TTF-1) is routinely tested in the diagnostic evaluation of suspected lung cancers, is commonly expressed by lung adenocarcinomas, and may modulate lung cancer biology. We examined the role of TTF-1 as a predictive and prognostic marker in patients with advanced lung adenocarcinomas. MATERIALS AND METHODS: We analyzed clinical, pathologic, and molecular features, treatments received, and overall survival obtained from the medical records of 479 consecutive patients at a single site with stage IV lung adenocarcinomas and evaluable TTF-1 expression. TTF-1 expression was determined by immunohistochemistry using antibody 8G7G3/1. RESULTS AND CONCLUSION: TTF-1 expression was evaluable in 479 (75%) of all patients reviewed, and was positive in 383 (80%, 95% CI 76-83%). Clinicopathologic features were similar between TTF-1 positive and TTF-1 negative tumors, except EGFR mutations were more common in TTF-1 positive cases (24% vs 6%, p<0.001). In univariate analysis, overall survival was significantly longer in patients with TTF-1 positive versus TTF-1 negative tumors (18 months vs 9 months, p<0.0001). In multivariate analysis, TTF-1 positivity remained associated with better overall survival (HR=0.38, p<0.0001), exceeding the prognostic impact of Karnofsky performance status >/=80% (HR 0.62, p=0.0003) and receipt of first-line combination chemotherapy or targeted therapy (HR relative to first-line single agent chemotherapy 0.59, p=0.05 and 0.51, p=0.05 respectively). Both patients with TTF-1 positive and TTF-1 negative cancers had longer durations of initial therapy when treated with pemetrexed-based chemotherapy. In patients with advanced lung adenocarcinomas, TTF-1 expression is associated with better survival but is not predictive of distinct benefit from pemetrexed-based chemotherapy.